T cells bearing invariant ?? T cell antigen receptors (TCR) localize to distinct epithelial sites in the adult mouse where they interact with non-classical antigen presenting cells such as epithelial cells. Many of these ?? T cell populations do not express traditional costimulatory molecules such as CD28 suggesting that they may rely on signals delivered through novel receptor-ligand interactions. We have identified AMICA, a member of the junctional adhesion molecule family, as a costimulatory molecule for epithelial ?? T cells. AMICA is expressed on all ?? T cells and in vitro mitogen activation leads to upregulated surface expression. Among lymphoid cells, AMICA is preferentially expressed by ?? T cells although a small subpopulation of CD8+ ?? T cells also express AMICA after activation. Signals delivered through AMICA costimulate skin and intestinal ?? T cell proliferation and cytokine release but not activation of any ?? T cells or lymphoid ?? T cells. We will test the hypothesis that AMICA expressed by epithelial ?? T cells binds to a ligand expressed on damaged epithelial cells and that interaction between this novel receptor-ligand pair delivers costimulatory signals to the ?? T cell that are critical for participation in local immune responses including tissue homeostasis and repair. Together these studies should determine the roles of AMICA in the activation and function of epithelial ?? T cells and may be applicable for manipulation of ?? T cell responses in epithelial disorders. [unreadable] [unreadable]